P640: PIRTOBRUTINIB, A HIGHLY SELECTIVE, NON-COVALENT (REVERSIBLE) BTK INHIBITOR IN COMBINATION WITH VENETOCLAX±RITUXIMAB IN RELAPSED/REFRACTORY CLL: RESULTS FROM THE BRUIN PHASE 1B STUDY
Authors: L. E. Roeker, A. R. Mato, J. R. Brown, C. C. Coombs, N. N. Shah, W. G. Wierda, M. R. Patel, K. L. Lewis, M. Balbas, J. Zhao, N. C. Ku, J. F. Kherani, D. E. Tsai, B. Nair, C. Y. Cheah
Journal: HemaSphere (2022)

Background: Covalent Bruton tyrosine kinase inhibitors (BTKi) have transformed the management of chronic lymphocytic leukemia (CLL), but patients (pts) discontinue these agents due to resistance or intolerance. Pirtobrutinib is an oral, highly selective, non-covalent (reversible) BTKi with promising efficacy and safety in heavily pretreated relapsed/refractory (R/R) CLL pts, regardless of BTK C481 mutation status. Recent clinical studies reported on the safety and efficacy of time-limited venetoclax and covalent BTKi combination regimens. Aims: We evaluated the safety and efficacy of pirtobrutinib combined with venetoclax ± rituximab in pts with R/R CLL. Methods: BRUIN is a phase 1/2 global, multicenter study (NCT03740529) of pirtobrutinib in pts with advanced B-cell malignancies. The phase 1b portion evaluated the safety of pirtobrutinib at a continuous dose of 200 mg QD from Cycle 1, Day 1 plus venetoclax starting on Cycle 2, Day 1 with a standard 5-week dose ramp to 400 mg QD (PV) and PV plus rituximab at 375 mg/m2 on Cycle 1, Day 1, then 500 mg/m2 on Day 1 of Cycles 2-6 (PVR). Prior BTKi was allowed; prior venetoclax was not permitted. Objectives included safety and overall response rate (ORR) of each combination. Results: As of 27 SEP 2021, 15 pts received PV and 10 pts received PVR. Median age was 66 years (range, 39-78). Median prior lines of therapy was 2 (range, 1-4). The majority of pts in both cohorts had received prior chemotherapy (56%, n=14), CD20 monoclonal antibody (72%, n=18), and/or covalent BTKi (68%, n=17). No dose-limiting toxicities were reported. Safety profiles were generally similar across both cohorts. The most common treatment-emergent adverse events (TEAE) of any grade, regardless of attribution, were neutrophil count decrease (36%), nausea (32%), fatigue (32%), diarrhea (28%), and constipation (24%). The only Grade ≥3 TEAE to occur in more than 2 pts was neutrophil count decrease (36%, n=9). One pt experienced Grade 4 clinical tumor lysis syndrome with resultant acute kidney injury during venetoclax dose escalation, which resolved with supportive measures. No pts discontinued treatment due to AEs. For the 22 pts with efficacy data available as of 03 NOV 2021, median duration of follow-up was 9 months (range, 3.9-15) and the ORR was 95.5% (95% CI, 77-100). All responding pts except 1 remain on therapy (PVR responder discontinued due to death unrelated to study treatment). As all responses were ongoing and early, and MRD analysis was not yet performed. Summary/Conclusion: Pirtobrutinib combined with venetoclax ± rituximab was well tolerated and had a safety profile consistent with known drug class findings and no clear additive toxicities in pts with R/R CLL. Early results demonstrate promising efficacy with combination therapy.